humulin-s and Glucose-Intolerance

To examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and β-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT).. Forty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up.. IT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 ± 1.4 (mean ± SD) to 1.72 ± 0.8, a level comparable to the IGT (1.96 ± 1.1) and NGT (1.37 ± 0.6) subjects in the remission group; however, no HOMA-IR improvement was observed in nonremission subjects. HOMA-β in the remission group was improved (mean, interquartile range) from 18.4 (8.3-28.5) to 44.6 (32.1-69.1) and acute insulin response of insulin (AIRins) from 1.50 ± 0.22 to 1.83 ± 0.19 μIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-β: 86.4 [56.7-185.2], P < 0.01; AIRins: 2.54 ± 0.39 μIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-β and HOMA sensitivity of remission subjects shifted close to that of IGT subjects.. IT in newly diagnosed type 2 diabetes not only partially restored β-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, β-cell function was less restored than insulin sensitivity after IT in the remission subjects.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Insulin, Isophane; Insulin, Regular, Human; Isophane Insulin, Human; Male; Middle Aged

Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels.. ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp.. Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline.. In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

Topics: Angiopoietin-Like Protein 8; Blood Glucose; Eating; Fasting; Glucose; Glucose Intolerance; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Nutrients; Peptide Hormones; Prediabetic State

To evaluate changes in insulin physiology in euglycemic pregnancy and gestational diabetes mellitus (GDM).. Participants underwent oral glucose tolerance tests at ≤15 weeks' gestation (early pregnancy), 24-32 weeks' gestation (mid-late pregnancy), and 6-24 weeks postpartum. We evaluated longitudinal changes in insulin secretory response (log Stumvoll first-phase estimate) and insulin sensitivity (log Matsuda index) using linear mixed models. We then evaluated participants who met GDM criteria in early pregnancy (early GDM) and mid-late pregnancy (classic GDM) separately from those without GDM. We derived the pregnancy insulin physiology (PIP) index to quantify β-cell compensation for insulin resistance.. Among 166 participants, 21 had early GDM and 24 developed classic GDM. Insulin sensitivity was reduced slightly in early pregnancy (β = -0.20, P < 0.001) and substantially in mid-late pregnancy (β = -0.47, P < 0.001) compared with postpartum. Insulin secretory response (adjusted for insulin sensitivity) was augmented in early pregnancy (β = 0.16, P < 0.001) and mid-late pregnancy (β = 0.16, P = 0.001) compared with postpartum. Compared with postpartum, the PIP index was augmented in early pregnancy (β = 215, P = 0.04) but not mid-late pregnancy (β = 55, P = 0.64). Early GDM was distinguished by a substantial reduction in early pregnancy insulin sensitivity (β = -0.59, P < 0.001) compared with postpartum. Both early and classic GDM lacked evidence of early pregnancy augmentation of insulin secretory response (adjusted for insulin sensitivity) and the PIP index (P > 0.1 vs. postpartum). Early pregnancy PIP index predicted GDM independent of participant characteristics (area under the curve without PIP index 0.70 [95% CI 0.61-0.79], area under the curve with PIP index 0.87 [95% CI 0.80-0.93]).. β-Cell function is enhanced in early pregnancy. Deficient first-trimester β-cell function predicts GDM.

Topics: Blood Glucose; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Postpartum Period; Pregnancy

Long-term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We used a liver-specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin receptor (INSR) and GCGR cross talk. RictorΔLiver mice were characterized by impaired AKT signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/βSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell-autonomous cross talk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.

Topics: Animals; Glucose; Glucose Intolerance; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt; Rapamycin-Insensitive Companion of mTOR Protein; Receptor, Insulin; Receptors, Glucagon; TOR Serine-Threonine Kinases

SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout (pSENP1-KO) mice on a high-fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were identical in pSENP1-KO and wild-type littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell-specific SENP1 KO mice. These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca

Topics: Animals; Cysteine Endopeptidases; Diet, High-Fat; Gene Expression Regulation; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeodomain Proteins; Incretins; Insulin-Secreting Cells; Insulin, Regular, Human; Mice; Mice, Knockout; Trans-Activators